The membranes of normal red cells and irreversibly sickled cells (ISCs) are being compared at the ultrastructural and biochemical level. Ultrastructural-histochemistry using 3,3'-diaminobenzidene reveals that more hemoglobin (Hb) remains attached to the ISC ghosts than to ghosts from normal erythrocytes. This may, in turn, alter the protein organization within the ISC membrane. Use of cross-linking reagents and gel electrophoresis has shown that the ISC membrane proteins form cross-linked aggregates more readily than do the proteins from normal red cells. In addition, we have found a protein of 60,000 MW in the ISC membranes that has intra-chain disulfide bonds in the living cell whereas these bonds are absent in the normal red cell membranes. This altered protein organization in the ISC membrane may play some role in explaining our recent finding that 51Cr labeled ISCs bound to cultured calf endothelium far better than did normal erythrocytes. This increased adhesivity may play a major role in the vaso-occlusive "painful crsis" syndrome of patients with sickle cell anemia.